Project Summary Chronic asthma affects millions of people in the United States, and nearly 40% of the asthma patient population is obese and exhibit increased asthma symptoms and severity. Obesity is associated with inflammatory and metabolic changes that can contribute to asthma pathobiology. Specifically, systemic metabolic changes in the obese patient, including increased levels of leptin, a pro-inflammatory mediator secreted by adipose tissue, and decreased responsiveness to glucagon-like peptide 1 (GLP-1), a gut hormone that regulates insulin production may augment pathogenic processes in asthma by acting directly on structural cells in the airway. Airway remodeling describes airway structural changes in asthma that can result in permanent airway obstruction. Airway fibroblasts contribute to this process by migrating to the sub-mucosa, where they proliferate and secrete extracellular matrix. The mechanisms directing airway remodeling in obese asthma are particularly poorly understood, but in allergic asthma, airway remodeling is directed in part by the key TH2 cytokine, interleukin-13 (IL-13). We have shown that IL-13 significantly stimulates airway fibroblast invasion in asthma compared with non-asthma subjects and that this effect is augmented in obese patients. Preliminary data that we present here suggest that leptin enhances airway fibroblast invasion and matrix production and that GLP-1 blocks these effects. Our overarching hypothesis is that leptin and GLP-1 play an important role in the development of airway fibrosis in allergic asthma, providing a link between obesity, glucose metabolism and asthma. The studies described in this proposal will test this hypothesis by identifying the mechanism of leptin-directed pro-fibrotic responses in airway fibroblasts in obese asthma (Aim 1), defining the role of GLP-1 in blocking allergen-induced airway fibrotic processes (Aim 2) and, determine the impact of bariatric surgery and weight loss on airway fibrosis in obese asthma (Aim 3). Successful completion of these Aims will not only increase our understanding of the unique cellular and metabolic mechanisms directing the pathobiology of obese asthma, but will also test specific interventions to treat obese asthma patients.